This proposal is based on a novel mechanism linking advanced age to destructive periodontal inflammation, which is targeted for new therapeutic intervention against periodontitis. The application therefore addresses the second thematic area of RFA-OD-10-005, Translating Basic Science Discoveries into New and Better Treatments. Old age is associated with increased prevalence and severity of certain chronic inflammatory diseases, including periodontitis. This oral inflammatory disease can lead to tooth loss and, moreover, exerts a systemic impact on the patients. However, current clinical periodontal treatment is often not sufficient on its own to control destructive inflammation. This necessitates improved therapeutic approaches, especially in the elderly who are more susceptible to periodontitis. In this regard, preliminary studies have identified a major mechanism linking advanced age to uncontrolled periodontal inflammation, attributed to age-associated deficiency of a molecule (termed Del-1 for developmental endothelial locus-1) that regulates the accumulation of neutrophils and associated inflammatory activity in the periodontal tissue. This regulatory homeostatic function involves the ability of Del-1 to bind and block the leukocyte-associated antigen-1 (LFA-1). Importantly, Del-1 deficiency leads to dramatic periodontal bone loss in a preclinical animal model. The destructive effects of neutrophils in periodontitis can be mediated either directly or indirectly via their ability to chemotactically recruit T-helper 17 (Th17) cells, which can cause chronic bone immunopathology mainly via interleukin-(IL)-17 production. This study was designed to provide proof-of-concept evidence that Del-1 treatment (as a fusion protein with the IgG Fc fragment;Del-1-Fc) in advanced age can reduce the excessive accumulation of neutrophils to the periodontium and inhibit destructive periodontal inflammation. At a first stage, this interventional study necessitates the use of an appropriate preclinical animal model. The specific aims are to show that (1) treatment of old mice with Del-1-Fc inhibits excessive neutrophil recruitment to periodontal tissues and leads to reduced inflammation and Th17-like activity;(2) treatment with Del-1-Fc inhibits periodontal disease in old mice;and (3) to compare Del-1-Fc with antagonists of LFA-1 and IL-17 for therapeutic treatment of periodontitis. The latter will help determine whether Del-1-Fc is sufficient on its own or whether it needs to be supplemented with antagonists of LFA-1 and/or IL-17A for maximum protection against periodontitis. This is probably the first time that an age-associated deficiency in periodontal innate immune regulation has been identified and a promising therapeutic intervention has been proposed. The long-term goal is to therapeutically exploit Del-1 to effectively complement current periodontal treatment and revolutionize the way elderly periodontal patients are managed. Moreover, Del-1-Fc may have wider applications given the destructive effects of uncontrolled leukocyte trafficking in various inflammatory and autoimmune conditions. PUBLIC HEALTH RELEVANCE: Conventional periodontal treatment is often not sufficient by itself to control destructive inflammation. We have discovered a major mechanism linking advanced age to uncontrolled periodontal inflammation, attributed to age-associated deficiency of a molecule (termed Del-1 for developmental endothelial locus-1) that regulates the accumulation of neutrophils and associated inflammatory activity in the periodontal tissue. Our objective is to therapeutically exploit Del-1 to correct age-associated Del-1 deficiency and thereby prevent destructive periodontal inflammation.